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PubMed1979

Antimalarials. 11. Synthesis of 3- and 5-aminoquinolines as potential antimalarials.

A series of 3-quinolinediamines (1g, 2c, and 3e) structurally related to primaquine and 4-methylprimaquine have been prepared and tested for antimalarial activity against Plasmodium berghei in mice and antileishmanial activity against Leishmania donovani in the hamster. All were inactive. In addition, three 5-quinolinediamines (4b, 5, and 6) were prepared. All were inactive against Leishmania donovani in hamsters. One of the examples, 6, was curative against Plasmodium cynmolgi in the rhesus monkey.

Aminoquinolines↗
PubMed1977

Antimalarials. 10. Synthesis of 4-substituted primaquine analogues as candidate antimalarials.

Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues of I. In addition, three side-chain analogues of II were prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in the Rane mouse screen and for radical curative activity against Plasmodium cynomolgi in the rhesus monkey. Four of the 17 compounds prepared (1a, 9c, 15, and 17) exhibited activity in at least one of the test systems.

Animals↗
PubMed1976

Antimalarials. 8. Synthesis of amino ethers as candidate antimalarials.

Based upon the antimalarial activities demonstrated by compounds I and II a series of amino ethers represented by structures III-VI was synthesized. These structures incorporated several modifications of compound II. The compounds prepared displayed no activity in either the Rane P. berghei mouse screen or the Rane P. gallinaceum sporozoite-induced chick test.

Amines↗
PubMed1975

Antimalarials. Synthesis and antimalarial activity of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine and derivatives.

The preparation and activity against Plasmodium berghei of derivatives of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine are described. Replacement of the cinnamoyl group was accomplished by acylation or alkylation of 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine. Modifications of the 5-phenyl group were prepared either by a sequence of reactions involving mandelic ester-pemoline-piperazine pemoline or by the reaction of 5-aryl-2-thio-2,4-oxazolidinedione with piperazine or N-substituted piperazines. In a similar manner, pemoline was allowed to react with N-arylpiperazine, hexahydro-1H-1,4-diazepine, and 2,6-dimethylpiperazine to provide N-arylpiperazine pemoline derivatives and variations in the piperazine moiety. Several compounds in which the 2-oxazolin-4-one ring was replaced with other heterocyclic rings were prepared as were several open-chain analogs. Five compounds (three of them substituted in the para position of the 5-phenyl group and two N-arylpiperazine pemoline derivatives) were found to be active against Plasmodium berghei. The remaining active compound possessed changes in the cinnamoyl group and substitution on the 5-phenyl group.

Animals↗
PubMed1975

Quinoxaline studies. 23. Potential antimalarials. Substituted 5,8-dimethoxy-6-[N-(omega-dimethylaminoalkyl)amino]quinoxalines were prepared: the first series with identical 2,3-substituents H, CH3, C6H5, C6H4-4-Cl, and CH2C6H5; and the second with identical styryl groups CH=CHC6H5, CH=CHC6H4-4-Cl, CH=CHC6H3-3,4-Cl2, CH=CHC6H4-4-F, CH=CHC6H4-4-CF3, and CH=CHC6H4-4-NO2. None of the substances possessed antimalarial activity; several were toxic at highest dosage levels.

3-Hydrazinopyridazines substituted in position 6 with a primary amine, secondary amine, or an alkoxy group were synthesized and screened for antihypertensive activity. In general, the 6-dialklamino derivatives are the most active; the (2-hydroxypropyl)methylamino chain provides the best combination of high antihypertensive activity and toxicity.

Animals↗
PubMed1992

Overview: clinical pharmacology of antimalarials.

The effectiveness of antimalarials depends on its pharmacodynamics ie inhibitory effect on the parasites and unwanted effects on the host. It also depends on the pharmacokinetics of the drugs. The ideal antimalarials are drugs that show curative activity in the absence of toxicity to the host. Recommendation for antimalarial dosage regimens should be based on pharmacokinetic and pharmacodynamic studies in appropriate populations ie ethnic groups, adults children, and in pregnancy. Chloroquine remains the drug of choice for treating malaria caused by Plasmodium species other than P. falciparum. Even in the presence of chloroquine resistance the drug may still be quite useful, especially in areas with high communal immunity. In general sulfadoxine/pyrimethamine (S/P) should be used as an alternative antimalarial when chloroquine fails. The decision to change to S/P from chloroquine depends on many factors. Quinine still remains the drug of choice for severe chloroquine-resistant falciparum malaria. Resistance to mefloquine has appeared the exact mechanism being unknown. In general, before the use of any combination of antimalarial drugs the superiority (efficacy and side-effects) over each of the individual drugs should be clearly demonstrated. The combination of mefloquine with sulfadoxine/pyrimethamine was made on the grounds that the combination would delay the resistance to mefloquine. Desferrioxamine will hardly be an agent to be used on its own for treating malaria due to the high recrudescent rate. However, a recent report indicated that its association with antimalarial drugs in the management of severe and complicated falciparum malaria shortens fever and parasite clearance time and resolves complications faster than the standard antimalarial drug alone. Clinical trials with halofantrine has been done in several countries in the region from 1988 to the present with diverse results. Further studies on a larger scale should be carried out to ascertain whether these are due to variation in drug absorption or drug resistance. An improved formulation of halofantrine must be developed to ensure adequate absorption and bioavailability. The artermisinin group of antimalarials is known to be highly effective and independent, in its mode of action, from standard malaria drugs but associated with high recrudescent rate. Phase II studies are needed for determining/optimizing therapeutic dose regimens and to ensure safer and more effective use of these compounds.

Antimalarials↗
PubMedDate not supplied

The antimalarial effect of iron chelators: studies in animal models and in humans with mild falciparum malaria.

In this study we explore the antimalarial effects of 3-hydroxypyridin-4-ones (CP compounds), a family of bidentate orally effective iron chelators in experimental animal systems in vivo and in vitro, and examine whether the iron chelator deferoxamine (DF) is active against human infection with P. falciparum. There was direct relation between lipid solubility of the CP compounds, which would facilitate membrane transit, and their in vivo antimalarial action, suggesting direct intracellular iron chelation as the most likely explantation for the antimalarial effect of iron chelators. Results of the double-blind, placebo controlled trial of DF in humans with asymptomatic parasitemia provided unequivocal evidence that this iron-chelating agent has antimalarial activity. Depriving the parasite of a metabolically important source of iron may represent a novel approach to antimalarial drug development. DF is a relatively ineffective intraerythrocytic chelator, and our data indicate that other orally effective iron chelators may have superior antimalarial activity in vivo. A systematic screening of available iron chelating drugs may result in the identification of potentially useful antimalarial compounds.

Animals↗
PubMed1992

The combined effect of iron chelators and classical antimalarials on the in-vitro growth of Plasmodium falciparum.

The emergence of drug resistant malaria has prompted an intensified search for new antimalarials or combinations of such drugs. Iron chelating agents may represent a new approach to antimalarial treatment and could possibly be used in combination with classical antimalarials. Plasmodium falciparum (FCR-3) strain used at a 1% haematocrit, was subjected to various combinations of the classic antimalarials (chloroquine, pyrimethamine and quinine) and iron chelating agents (desferrioxamine and 2,2'-bipyridyl) in vitro. Tritiated hypoxanthine incorporation was used to determine the growth of the malarial parasites. The iron chelating agents and classic antimalarials when tested alone were found to inhibit the growth of the late stages of the parasite. The combination of the classic antimalarials and iron chelating agents resulted in additive effects on the in-vitro growth of P. falciparum.

Animals↗
PubMed1975

The efficacy of antimalarials in systemic lupus erythematosus.

Of 209 patients who fulfilled the A.R.A. criteria for the diagnosis of systemic lupus erythematosus, 43 were selected for study because each had been treated for at least two years with antimalarials, but had not received antimalarials for at least one subsequent year. In each instance, the antimalarial was discontinued solely because of the development of retinopathy. Each year on antimalarials was matched with a subsequent year off antimalarials for each patient. The year immediately following diagnosis and years of pregnancy were excluded. Paired-t test analysis of matched years revealed that general symptoms (fever, fatigue, weight loss) were less common during years on 500 mg chloroquine daily than during years off the drug (p less than 0.05). Skin manifestations were also less frequent during the years on 500 mg chloroquine daily than during the years off (p less than 0.05). No significant steroid sparing effect was found. However, a greater incidence of flare-ups during the matched years off the drug was statistically significant.

Adolescent↗
PubMed1990

Parasite uptake of desferroxamine: a prerequisite for antimalarial activity.

Desferroxamine has been shown to exhibit potent antimalarial activity. However, it is unclear as to whether desferroxamine functions by the chelation of extracellular, intra-erythrocytic, or parasite-associated iron. In order to determine desferroxamine's site of action, we have employed a large molecular weight dextran derivative of desferroxamine (70 kDa) and a reversible osmotic lysis technique by which erythrocytes were intracellularly loaded with this chelator. The desferroxamine-dextran derivative has virtually identical iron-binding characteristics to desferroxamine but, unlike desferroxamine, it is unable to cross the erythrocyte membrane. As previously shown, desferroxamine added to culture media exhibited potent antimalarial activity (mean effective inhibitory dose (ED50) approximately 6 microM). However, extracellular desferroxamine-dextran showed antimalarial activity only at very high doses (ED50 greater than or equal to 180 microM), indicating that extracellular iron chelation is not involved in the antimalarial activity of desferroxamine. The intra-erythrocytic entrapment of the desferroxamine-dextran derivative also had no significant effect, except at very high concentrations, demonstrating that desferroxamine does not remove a non-haem iron source necessary for malarial replication. The results of this study clearly suggests that the antimalarial activity of desferroxamine is directly related to its ability to enter the parasitic compartment and not due to the chelation of extra- or intra-erythrocytic iron pools necessary for malarial growth.

Animals↗
PubMed1992

Extraordinarily potent antimalarial compounds: new, structurally simple, easily synthesized, tricyclic 1,2,4-trioxanes.

New, racemic, tricyclic trioxane alcohol 3 was designed and synthesized as a structurally simple analog of clinically useful, tetracyclic, antimalarial artemisinin. A series of 20 ester and ether derivatives of alcohol 3 were prepared easily, without destruction of the essential trioxane system. Chemical structure-antimalarial activity for each derivative was evaluated in vitro against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum parasites. Many of these derivatives were highly efficacious; carboxylate ester 9f, carbamate ester 10a, and sulfonate ester 12a had antimalarial potency similar to that of artemisinin, and carboxylate esters 9b and 9d, carbamate esters 10b and 10c, and phosphate esters 11a-c had antimalarial potency up to 7 times higher than that of artemisinin. Several of these most active analogs (e.g., carboxylate 9b and carbamates 10a and 10c) are stable crystalline solids, a feature of considerable practical value for any new drug candidate.

Animals↗
PubMed1979

Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.

A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound tested. The applications and expectations of this new test system within a drug development program are discussed.

Animals↗
PubMed1992

Antimalarial activity of new dihydroartemisinin derivatives. 5. Sugar analogues.

A series of dihydroartemisinin derivatives containing a sugar moiety was prepared in the search for analogues with good water solubility and high antimalarial activity. The preparation of the new compounds was achieved by treatment of dihydroartemisinin (2) with chlorotrimethylsilane in pyridine solution at -10 degrees C to give a nearly quantitative yield of 10-O-(trimethylsilyl)dihydroartemisinin (3), which was then condensed with 1-hydroxypolyacetylated sugars 5 to give dihydroartemisinin derivatives 7a-d. Deacetylation of intermediates 7 gave the desired sugar derivatives 8. The resulting derivatives, tested in vitro against Plasmodium falciparum, were found to be more effective against W-2 than D-6 clones and were not cross-resistant with existing antimalarials. Trimethylsilylated compound 3 is more effective than derivatives 7a-d, which possess activity comparable to or better than that of artemisinin itself. Deacetylated compounds 8a-d were substantially less active than 7 in both cell lines. In P. berghei-infected mice, 7a-c showed 5/5, 2/5, and 3/5 cures, respectively, at 320 mg/kg per day x 3, whereas 7d showed no activity at the same dosage. However, 7d did prolong the life span in 3/5 of the infected mice at 640 mg/kg per day x 3 dose level. Trimethylsilylated compound 3 was also the most effective among the compounds studied, with 5/5 cures at 80 mg/kg per day x 3. The deacetylated sugar derivatives 8a-d showed only slight in vivo antimalarial activity.

Animals↗
PubMed2025

Strategies for mitigating emerging artemisinin-based antimalarial drug resistance in Rwanda: a promising approach for managing therapies in malaria-endemic countries.

Malaria treatment failures associated with reduced efficacy of chloroquine (CQ) and amodiaquine (AQ) antimalarial drugs emerged in Rwanda during the 1980s, prompting the policy shift towards adopting artemisinin-based combination therapies in 2006 as an alternative. However, recent findings from malaria surveillance and therapeutic efficacy studies have revealed a countrywide increase in antimalarial drug resistance. Particularly, artemether-lumefantrine (AL) efficacy has significantly decreased, probably due to the emergence of Plasmodium falciparum (Pf) genomic mutations. To mitigate the current drug resistance, Rwanda has adopted targeted multiple first-line therapies. Through the national malaria control program, antimalarial drugs were deployed in accordance with the reported resistance profile. A significant rise in Pfkelch13 mutations, particularly A675V associated with AL resistance, was mainly reported in the western region; therefore, artesunate-pyronaridine was recommended. Dihydroartemisinin-piperaquine was considered in eastern and central regions, where R561H mutations were predominant. On the contrary, AL was maintained in the southern region, where the prevalence of the R561H mutation was low. Insights from this data-driven model will inform its extension to other malaria-endemic countries facing emerging Pf genetic diversity.

Antimalarials↗
PubMed1979

Antimalarial activity of Floxacrine (HOE 991) I. Studies on blood schizontocidal action of Floxacrine against Plasmodium berghei, P. vinckei and P. cynomolgi.

Floxacrine (HOE 991), 7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)3,4-dihydroacridine-1,9-(2H, 10H) dion, shows a high level of antimalarial action against blood-induced infection of drug-sensitive and drug-resistant lines of Plasmodium berghei in mice, rats and Syrian hamsters. The drug is also a potent blood schizontocide against drug-sensitive P. vinckei strains in rodents and P. cynomolgi in rhesus monkeys. The CD50/CD90 values against the drug-sensitive P. berghei strain ascertained in the '28-day test' in mice were 4.3/6.7 mg/kg after the oral route and 1.7/3.6 mg/kg after the subcutaneous (sc) route. In the 'two- and four-day test' the ED50 against sensitive P. vinckei was 0.7 mg/kg in both mice and rats. A moderate prophylactic effect could be demonstrated after the sc route probably due to a 'depot effect' of the water-insoluble active principle. Floxacrine was also highly active against P. berghei-lines which were resistant to chloroquine, mepacrine, dihydrofolate reductase inhibitors, sulfadoxine and dapsone. Resistance to HOE 991 could be developed in P. berghei and P. cynomolgi when the compound was used alone and administered repeatedly in subcurative doses. The antimalarial activity of the compound was not influenced by p-aminobenzoic acid or folic acid supplements in diets. Structural changes induced by floxacrine on pigment cytoplasm and nucleus in erythrocytic stages of P. berghei differed in some aspects from those of mepacrine and chloroquine. It is therefore assumed that the mode of action of floxacrine differs from that of the known antimalarial drugs. The general tolerance of the compound in rodents and rhesus monkeys is good and there is a wide range between the effective and maximum tolerated doses. Floxacrine was also effective at 100 ppm against pathogen Eimeria species in chickens, at 1000 mg/kg orally against Fasciola hepatica in rats and at 300-800 mg/kg orally against Heterakis spumosa in rats.

4-Aminobenzoic Acid↗
PubMed1975

Synthesis and antimalarial activity of heterocyclic alkyl disulfides, thiosulfates, and dithio acid derivatives.

Based on the antimalarial activity in mice of bis(4-rho-acetamidobenzenesulfonamidophenyl) disulfide, a series of N-heterocyclic alkyl disulfides and thiosulfates was synthesized and screened for antimalarial activity. Several related dithio acid dianions and S- blocked derivatives were also screened to provide an indication of the possible role that thiol anions might play in malaria chemotherapy. Activity was limited by toxicity with these compounds, and none of those tested, with the exception of bis(4-rho-acetamidobenzenesulfonamidophenyl) disulfide, showed curative activity in either a mouse or chick test.

Animals↗